Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

●vascular alterations

●senile ocular pigment degeneration

●cystic degeneration

●retinoschisis

●latex degeneration

●cobblestone degeneration

Here are briefly described the major characteristics of these diseases.

Senile Cataracts

The lens is exposed to the cumulative effects of radiation, oxidation, and translational modification. The alteration of proteins and other lens molecules impairs membrane functions and perturbs protein (particularly crystallin) organization, so that light transmission and image formation may be compromised. Damage is minimized by the presence of powerful scavenger and chaperone molecules. Progressive insolublization of the crystallins in the lens nucleus in the first five decades of life, and the formation of higher molecular weight aggregates, may account for the decreased deformability of the lens nucleus that characterizes presbyopia.

Additional factors include the progressive increase in lens mass with age, changes in the point of insertion of the lens zonules, and a shortening of the radius of curvature of the anterior surface of the lens. There is also a decrease in light transmission by the lens with age, associated with increased light scatter, increased spectral absorption (particularly at the blue end of the spectrum), and increased lens fluorescence. A major factor responsible for the increased yellowing of the lens is the accumulation of a novel fluorogen—glutathione-3-hydroxy kynurenine glyco- side—which makes a major contribution to the increasing fluorescence of the lens nucleus that occurs with age. Because this compound may also crosslink with the lens crystallins, it may contribute to the formation of high-molecular weight aggregates and the increases in light scattering that occur with age. Focal changes of microscopic size are observed in apparently transparent, aged lenses, and may be regarded as precursors of cortical cataract formation.

Senile Detachment of the Retina

It is not easy to define retinal detachment as senile. There are chorioretinal and vitreal alterations that are typically geriatric, and may cause detachment of the retina.

Cystic Degeneration of the Periphery of the Retina

On the one hand, cystic degeneration causes a thinning and weakening of the retina and on the other hand favors the formation of pathological adherence with the

vitreo, and therefore creates a predisposition to retinal rupture at the margin or at the operculum. Furthermore, the walls of the cysts may break and therefore retinal holes may form.

Paved, Cobblestone or Pavement Degeneration as Proposed by Straatsma8 or Gonin’s Foci of Atrophic Choroidosis

From a histological point of view, these lesions show the disappearance of the choriocapillaries and the pigment epithelium, or atrophy of the inner layers of the retina—i.e. those that depend on the trophism of the choriocapillaries for nutrition. The retina is strongly held to the choroid in these degenerative foci. They almost never form holes or ruptures of the retina. This type of degeneration does not favor the detachment of the retina per se, but shows that there is wear and choroidal and retinal degeneration at the periphery that may favor the onset of retinal detachment. In fact, O’Malley and Allen9 observed that numerous patients who show cobblestone degeneration also have cystic degeneration of the retina, fence degeneration, retinoschisis, retinal holes and ruptures, and cysts of the pars plana near these lesions.

Senile Degeneration of the Vitreous

After 50 years of age, a fibrillar and lacunar degeneration of the vitreous begins in emmetropic eyes, slowly progressing and possibly resulting in the posterior detachment of the vitreous with its collapse. This is a typical senile disease that is found in 65 percent of individuals over 65 years old and more or less 100 percent of individuals over 77 years. The posterior detachment of the vitreous may cause, where there is an adherence between the vitreous and the retina, rupture of the retina by traction. The retinal rupture may be secondary to a choroidal exudation of congestive or allergic inflammatory origin that passes the pigment epithelium, applying pressure to the retina towards the inside of the eye bulb, causing its rupture at a weak point. Upon contact with the choroidal exudation liquid, the vitreous then coagulates. Senile retinal detachment seems to be essentially caused by cystic degeneration of the retina, and posterior detachment of the vitreous with collapse. This is due to the fact that in cases of senile detachment, posterior detachment of the vitreous with collapse is nearly always found. If we consider, however, the rarity of retinal detachment with respect to posterior detachment of the vitreous and cystic degeneration of the retina in senility, we must admit that many other factors must be relevant in retinal detachment, such as genetic predisposition, vascular- retinal-choroidal factors, and abiotrophic factors.

The changes that lead to retinal detachment in senile eyes are very similar to those in myopic eyes. A study performed on 829 patients affected by retinal detachment and surveyed over three years found that about 34 percent were myopic and 66 percent were not. Of these, around 63 percent were individuals more than 40

years old.10 This shows, therefore, that senility plays an important role in the initiation of retinal detachment. Without doubt, retinal detachment results from degenerative lesions of the retina and the choroid—lesions that normally do not have characteristics appreciably different from degenerative myopic lesions. In the case of senility, the lesions are related to obstructions of the retinal and sometimes choroidal capillaries.

The study of the cases in which the retinal detachment occurred in nonmyopic individuals in senile age groups confirms that normally in these degenerative lesions there is evidence of vascular obstruction in the form of thin, obliterated blood vessels that prevail in the superior temporal quadrant. In the eyes of nonmyopic senile-aged subjects, it is possible to see (more frequently than in young subjects) small pigmented equatorial spots that are often hexagonal in appearance. These are often the starting point of horseshoe ruptures, on the borders of which pigment deposits are found. Finally, there can be interruptions in the continuity of the macula deriving from senile alterations. In senile degeneration of the macula, pits may form in the macular lamella, which—although not very frequent—become perforations with consequent retinal detachment. Senility, as well as favoring the arrival of rhegmatogenous retinal alterations, is also responsible for the degenerative vitreol changes that can produce traction, rupture, and therefore detachment of the retina.11

Vascular Alterations

The influence of vascular alterations in the pathogenesis of senile retinal detachment must be taken into consideration. Because aging causes a reduction in cardiac and lung performance, it may also cause a decrease of the retinal integrity. A parallel can be seen between the athero-sclerotic lesions of the retinal blood vessels, and those of the other organs. We should remember that aphakia—not often seen these days, as a result of good cataract operations—has a tight correlation with retinal detachment. It originates from small ruptures or holes in the ora serrata. In senile aphakic eyes, retinal degeneration is very often seen at the periphery and particularly in the ora serrata with small holes generally located in the meridional folds of the retina.

Senile Peripheral Pigment Degeneration

Senile peripheral pigment degeneration is associated with wartiness of the Bruch’s membrane and sclerosis of the choroid. It is often bilateral. One type of pigment alteration that is not, however, comes from moniliform pigmented scratches of the chorioretina. These are pigment granules that seem to be localized on sclerotic choroidal blood vessels in the nasal inferior quadrant.12

Cystic Degeneration

The retina shows two types of cystic degeneration—typical and reticular. The first originates on the outer plexiform layer, while the second originates in the nervous fiber layer. These changes are very common after 70 years of age. The typical peripheral cystoid degeneration (TPCD), also called Blessig-Iwanoff cysts, is characterized by cysts of the outer plexiform layer containing hyaluronic acid that can also coagulate, producing a globular form with winding channels that branch irregularly. Complications are rare. The retinal holes do not produce detachment of the retina because the vitreous is normally complete over the lesion. The extension of the lesion beyond the equator is also rare. The breakage of the walls of the cysts or gaps causes the formation of peripheral lamellar holes. The retina is not detached and there is not the operculum of real retinal holes. Rare, but possible, is the formation of real retinal holes, with operculum to which vitreous body filaments adhere following a filamentous degeneration of the vitreous body and separating from the ora serrata. This can lead to another periferal alteration—degenerative retinoschisis. The second type of modification is retinal periphery cystoid degeneration, which is almost always continuous and located behind areas of typical peripheral cystiod degeneration, and is usually found in the inferotemporal quadrant. This has a reticular aspect that corresponds to the retinal vessels of the inner layers. A finely punctured inner surface corresponds to the attachment points of the tissue cushions to the inner layer. The cystic spaces are located in the nervous fiber layer. This process occurs in 18 percent of adults, and occurs in bilateral form in 41 percent. It can evolve into degenerative reticular retinoschisis.9

Retinoschisis

Two degenerative forms of retinoschisis have been described. They are both most frequently seen in the infero-temporal quadrant, and derive from a pre-existing form of peripheral cystoid degeneration. TPCD can evolve into typical degenerative retinoschisis, while both the typical and reticular forms of peripheral cystoid degeneration can transform into reticular degenerative retinoschisis.Typical degenerative retinoschisis causes a smooth raising of the retina in 1 percent of the adult population (bilateral in 33% of cases). Typical peripheral cystoid degeneration surrounds the lesions. The retina is divided along the outer plexiform layer, and consequently the inner layer comprises the ILM, the nervous fiber layer, the retinal vessels, the ganglion cells, the inner plexiform layer, and the inner nuclear layer. Normally, only the ILM, the nervous fiber layer, and part of the inner nuclear layer are visible. The outer layer is thicker, with cavities, and made up of the external nuclear layer and the photoreceptors.13 Reticular degenerative retinoschisis develops from the concurrent presence of typical and reticular cystoid degeneration of the peripheral retina. It is characterized by oval or round areas of detached retina,

in which a lump forms in the very thin inner layer, and is observed in 1.6 percent of the adult population (bilateral form in 15% of cases). Normally, typical peripheral cystoid degeneration is located anterior to the reticular degenerative retinoschisis, while the reticular form is adjacent.

The detachment occurs in the nervous fiber layer—the inner portion contains only the ILM, some retinal vessels, and a variable portion of the nervous fiber layer. The outer portion contains the remaining relatively complete retinal layers. Sometimes, typical and reticular retinoschisis are seen at the same time. It is not always easy to differentiate between the two forms on a clinical basis, unless there are lumpy aspects. The presence of holes in the outer margin or posterior extension is characteristically more common of the reticular form than the typical form.

Latex Degeneration

The frequency of latex degeneration was found to be 8 percent in an ample clinical study, and 10.7 percent in autopsy studies. The lesions are bilateral and symmetrical in 48.1 percent of the cases, and the frequency increases after the second decade of life. The majority of the lesions, located in the pre-equatorial region, are orientated according to the circumference and more frequently in the vertical meridian.14 Latex lesions appear like a thinning of the retina. They can also look like a plait caused by sclerotic vessels, and may have variable pigmentation resulting from hypertrophy of the retinal pigmented epithelium (RPE). Histological latex degeneration is characterized by an overlying sack of vitreous fluid, absence of the ILM, vitreous condensation at the margins, hyperplasia of the glial cells and at the edges of the RPE (in some cases), thinning and the formation of retinal holes at the center of the lesion, sclerosis of the major blood vessels, sclerosis and a-cellularity of the capillaries’ hypertrophy, and hyperplasia of the RPE.

Cobblestone Degeneration

This common degenerative chorio-retinal process is found in up to 27 percent of subjects after the 30th year. It is located between the ora serrata and the real side of the equator, and represents a boundary zone between the posterior choroidal circulation and the anterior ciliar circulation. Opthalmoscopically, it looks like a small and discrete yellow-white area, with very visible choroidal blood vessels— sometimes with hypertrophic and dark RPE at the margins. The lesions can join together to form a band of depigmentation behind the ora serrata. Histo-pathologic studies show signs of ischemic atrophy of the outer retina, with attenuation or disappearance of the choriocapillaries and loss of the RPE and the outer retinal layer up to and including the outer part of the inner nuclear layer. These changes are limited to the portion of the retina that is supplied by the choriocapillaries, and

can be reproduced in rabbits after binding the choriodal blood supply.8 Cobblestone degeneration is a characteristic that suggests peripheral vasculopathy and can be highly extended in carotid stenosis.9

Prevention

Considering what has been described above, prevention of the degenerative factors induced by aging points to the application of an anti-apoptotic action to the nervous cells and glia of the human retina. One possible drug to perform this is acetylcarnitine (ALCAR). In recent years, attention has been focused on the advantageous influence of carnitine as an anti-apoptotic agent—above all, as a molecule able to block the mitochondrial pathway in programmed cell death. Moreover, ALCAR seems to have a major protective role in senile retinal decay. The anti-apoptotic action caused by carnitine includes: induction of growth factors, increase in mitochondrial metabolism, protective action on the mitochondrial membrane integrity, inhibition of caspase activity, and, finally, an antioxidant activity.

References

1.Owsley C, Jackson GR, Cideciyan AV, Huang Y, Fine SL, Ho AC, Maguire MG, Lolley V, Jacobson SG (2000) Psychophysical evidence for rod vulnerability in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 41:267273

2.Armstrong D (1984) Free radical involvement in the formation of lipo-pigments. In: Armstrong D (ed) Free Radicals in Molecular Biology, Aging and Disease. Raven Press, New York, p 137-182

3.Brizee KR, and Ordy JM (1981) Cellular features, regional accumulation, and prospects of modification of age pigments in mammals. In: Sohal RS (ed) Ageing Pigments Elsevier/North

– Holland Biomedical Press, Amsterdam, p 176-181

4.Dykens JA (1999) Free radicals and mitochondria dysfunction in excyto-toxicity and neurodegenerative disease. In: Koliatos VE and Rantan RR (eds) Cell Death and Diseases of the Nervous System, Humana Press, Totowa, P 45-68

5.Handelman GJ and Dratz EA (1986) The role of antioxidants in the retina and retinal pigment epithelium and the nature of pro-oxidant induced damage. Adv. Free Radicals. Biol. Med. 2:1:89

6.Cavallotti C, Artico M, Pescosolido N, Feher J (2004) Age-related Changes in human retina. Can. J Ophthalmol. 39:61-68

7.Foulds WS (1980) Factors influencing visual recovery in retinal detachment surgery. Trans. Ophthalmol. Soc.U.K.100:72-77

8.Straatsma BR, Foos RY, Feman SS (1980) Degenerative diseases of the peripheral retina. In: Duane TD (ed) Clinical Ophthalmology. Harper & Row, Philadelphia, p 1-27

9.O’Malley PF, and Allen RA (1967) Peripheral cystoid degeneration of the retina. Incidence and distribution in 1,000 autopsy eyes. Arch. Ophthalmol. 77:769-776

10.Curcio CA, Millican CL, Allen KA, Kalina R.E (1993) Aging of the human photoreceptor mosaic: Evidence for selective vulnerability of rods in central retina. Invest. Ophthalmol. Vis. Sci. 34:3278-3296

11.Marshall J (1987) The ageing retina: physiology and pathology. Eye. 1: 282-295

12.De Laey JJ (1988) Ophtalmologie geriatrique. In: Oosterhosch (ed) Traité de Geriatrie,Sociéte Scientifique de Medicine Generale, Bruxelles, p 263-488

13.Foos RY (1970) Senile Retinoschisis: relationship to cystoid degeneration. Trans. Am. Acad. Ophthalmol. 68:329-403

14.Byer NE (1989) Long-term natural history of lattace degeneration of the retina. Ophthalmology. 96:1396-1402

The mitochondria are smaller and less numerous in these cells than in those in the non-pigmented epithelium. The basal side, facing the ciliary body, has a basement membrane—uniform in thickness—throughout their course.1 The basal cell membrane shows only a few in-folding. The cell membrane on the apical side is like that in the nonpigmented epithelium. There are numerous cell junctions. The lateral surfaces show numerous interdigitations.2

Micro-anatomical Details

The cells of the human RPE are post-mitotic cells, with an hexagonal shape, that form a single layer of cubic epithelial cells that separate the external portion of the photoreceptors from the choroid. The RPE provide metabolic and functional support for the external portion of the photoreceptors and all the remaining layers of the retina. Each human eye contains between 4 and 6 million RPE cells. In the central part of the retina, the shape and dimensions of the RPE cells are uniform. They are about 14 m in diameter and 12 m in height. At the equator, the cells are taller and larger, and at the extreme periphery lose their uniformity of size and shape. Some cells may contain more than one nucleus, and at the ora serrata, the RPE cells may measure up to 60 m in diameter These cells are formed from a basal portion, apical portion, and six lateral faces.3 The basal portion shows the cellular membrane with numerous invaginations, which can sink up to 1 m into the cytoplasm to increase the absorbent surface. The basal membrane of these cells is adjacent to the basal lamina that forms the proximal layer of the Bruch’s membrane. The basal invaginations increase the surface area of the cellular membrane, because this is involved in transport functions. The apical portion of the RPE cells that sits in front of the acromeres of the photoreceptors is folded to form micro-villa of 5-7 m in length that surround the third terminal part of the acromeres. Because the acromeres of the rods and cones are of different dimensions, the villa that surround the external portion of the rods are smaller (3 m) than those that surround the cones. From a functional point of view, there are two different types of micro- villa—one softer, which is dedicated to transepithelial transport, and the other connected to the distal lamina of the photoreceptors. The lateral portions of the RPE are linked (zonula occludens and adherens) to create the external hematoretinal barrier and are interconnected through intercellular junctions at the same time. The cells have a round basal nucleus, and the cytoplasm is rich in lysosomes, smooth endoplasmic reticulum, mitochondria at the basal level, round pigmented granules, and oval ones containing melanin. The majority of the melanin granules are found in the apical portion or in the villa. The granules measure up to 1 m in diameter and from 2 to 3 m in length. The pigment granules adsorb light, preventing diffusion, and also act as free radical scavengers. The RPE cells in the macular and equatorial regions contain a major quantity of pigment.4